Therapy of atherosclerosis, primary biliary cirrhosis and NRLP3 inflammasome-associated disease by HTCP inhibitors

a technology of htcp inhibitors and atherosclerosis, which is applied in the direction of peptide/protein ingredients, metabolism disorders, peptide sources, etc., can solve the problems of unresolved problems, major unmet medical needs, and limited success of existing plaque burden in patients with advanced symptomatic atherosclerosis, so as to improve primary biliary cirrhosis and reduce inflammation and fibrosis. the effect of progression

Active Publication Date: 2021-02-23
MYR
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Drug therapies that attempted to raise HDL cholesterol level or improve HDL functions have been investigated, but so far with limited success (Shih et al., 2013).
Despite the availability of treatment options, major unmet medical need exists in the treatment of atherosclerosis.
Especially, the reduction of existing plaque burden in patients with advanced symptomatic atherosclerosis is an unresolved issue.
Progressive bile-duct injury from portal and periportal inflammation could result in progressive fibrosis and eventual cirrhosis.
Furthermore, abnormal suppressor T-cell activity has been reported in asymptomatic first-degree relatives of affected individuals.
However, about 40% of patient treated with UDCA do not achieve adequate biochemical response.

Method used

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  • Therapy of atherosclerosis, primary biliary cirrhosis and NRLP3 inflammasome-associated disease by HTCP inhibitors
  • Therapy of atherosclerosis, primary biliary cirrhosis and NRLP3 inflammasome-associated disease by HTCP inhibitors
  • Therapy of atherosclerosis, primary biliary cirrhosis and NRLP3 inflammasome-associated disease by HTCP inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

an HTCP Inhibitor in APO-E Knock-Out Mice

[0373]Objective:

[0374]The objective of this study is the evaluation of the effect of an HTCP inhibitor Myrcludex B at various doses on physiology and atherosclerotic lesion development in APO-E knockout mice, an animal model that closely resembles the human atherosclerotic condition.

[0375]Methodology:

[0376]Test weeks 1-8:

[0377]Randomization and allocation to 4 test groups:

[0378]

Numberof animalsGroupsMaleFemale1 Control0552 Test ItemDose level 155

[0379]Administration: Daily s.c. injection

[0380]Special housing conditions:

[0381]

DietStandard diet for all study groups

[0382]Parameters to be determined:

[0383]

Clinical signsDailyMortality / MorbidityDailyBody weightAt start, weekly thereafter, at interim dissectionFood consumptionWeekly (mean values)Clinical biochemistryAll animalsAt dissectionUsing the Konelab 30i instrumentParameters: total bile acid LDL, HDL, VLDL,cholesterolDissection / NecropsyAll animalsDissection incl. macroscopic inspectionQuantit...

example 2

an HTCP Inhibitor in LDL Receptor Knock-Out Mice

[0385]Objective:

[0386]The objective of this 23 weeks study is the evaluation of the effect of an HTCP inhibitor Myrcludex B at various doses on physiology and atherosclerotic lesion development in LDL receptor-knockout mice (LDLRKO), an animal model that closely resembles the human atherosclerotic condition.

[0387]Methodology:

[0388]16 male and 6 female LDLRKO mice

[0389]8 weeks on high calorie diet

[0390]Sacrifice of 4 males and 4 females

[0391]Randomization of remaining animals to 4 groups

[0392]15 weeks on standard diet and daily s.c. Myrcludex B treatment starting on week 9

[0393]Species / Strain: Mouse LDLR Knock-Out / B6.12957-Ldlrtm1Her / J

[0394]Supplier: The Jackson Laboratory. USA

[0395]Test weeks 1-8:

[0396]

Number ofGroupsanimals1 Pool16 male + 16female

[0397]

DietHigh calorie diet in weeks 1-8

[0398]Parameters to be determined:

[0399]

Clinical signsDailyMortality / MorbidityDailyBody weightAt start, weekly thereafter, at interim dissectionFood co...

example 3

nical Trial in Patients with Dyslipidaemia with a HTCP Inhibitor Mycludex B

[0409]Objective:

[0410]The objective of the clinical trial is the evaluation of safety and tolerability, as well as efficacy of Myrcludex B in patients with dyslipidaemia.

[0411]Methodology:

[0412]20 patients with dyslipidaemia

[0413]8 weeks of Myrcludex B, 10 mg daily

[0414]Endothelial function examination, lipid panel and further biomarkers: assay of macrophage cholesterol efflux and ATP-binding cassette transporter genes ABCA1 and ABCG1.

[0415]Results:

[0416]Myrcludex B was well tolerated.

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Abstract

An inhibitor of Na+-taurocholate cotransporting polypeptide (NTCP) for use in a method of treatment of primary biliary cirrhosis, atherosclerosis, or an NRLP3 inflammasome-associated disease in a subject.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This application claims the priority to European Application Number 17 166 828.8 filed Apr. 18, 2017, the disclosure of which is incorporated herein in its entirety by reference.[0002]The present application includes a Sequence Listing filed in electronic format. The Sequence Listing is entitled “2185-371_ST25.txt” created on Jun. 27, 2018, and is 12,000 bytes in size. The information in the electronic format of the Sequence Listing is part of the present application and is incorporated herein by reference in its entirety.FIELD OF INVENTION[0003]The present invention pertains to novel therapy of atherosclerosis, primary biliary cirrhosis, or an NRLP3 inflammasome-associated disease. In particular, the invention provides NTCP inhibitors, preferably pre-S1 peptide inhibitors, and compositions comprising same, for the treatment of said diseases. Method of treatment of said diseases by NTCP inhibitors, preferably pre-S1 peptide inhibitors, are...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61P1/16A61K38/16A61K45/06C07K14/02
CPCA61K38/162A61K45/06A61P1/16C07K14/02A61K2300/00C12N2730/10122C12N2730/10133C12N2760/10122C12N2760/10133C07K14/005A61P9/10A61P25/28A61P3/10A61K38/08A61K38/10
Inventor ALEXANDROV, ALEXANDER
Owner MYR
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